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A phase I trial of docetaxel and pulse-dose 17-allylamino-17-demethoxygeldanamycin in adult patients with solid tumors

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Abstract

Purpose

To define maximum tolerated dose (MTD), clinical toxicities, and pharmacokinetics of 17-allylamino-17-demethoxygeldanamycin (17-AAG) when administered in combination with docetaxel once every 21 days in patients with advanced solid tumor malignancies.

Experimental design

Docetaxel was administered over 1 h at doses of 55, 70, and 75 mg/m2. 17-AAG was administered over 1–2 h, following the completion of the docetaxel infusion, at escalating doses ranging from 80 to 650 mg/m2 in 12 patient cohorts. Serum was collected for pharmacokinetic and pharmacodynamic studies during cycle 1. Docetaxel, 17-AAG, and 17-AG levels were determined by high-performance liquid chromatography. Biologic effects of 17-AAG were monitored in peripheral blood mononuclear cells by immunoblot.

Results

Forty-nine patients received docetaxel and 17-AAG. The most common all-cause grade 3 and 4 toxicities were leukopenia, lymphopenia, and neutropenia. An MTD was not defined; however, three dose-limiting toxicities were observed, including 2 incidences of neutropenic fever and 1 of junctional bradycardia. Dose escalation was halted at docetaxel 75 mg/m2-17-AAG 650 mg/m2 due to delayed toxicities attributed to patient intolerance of the DMSO-based 17-AAG formulation. Of 46 evaluable patients, 1 patient with lung cancer experienced a partial response. Minor responses were observed in patients with lung, prostate, melanoma, and bladder cancers. A correlation between reduced docetaxel clearance and 17-AAG dose level was observed.

Conclusions

The combination of docetaxel and 17-AAG was well tolerated in adult patients with solid tumors, although patient intolerance to the DMSO formulation precluded further dose escalation. The recommended phase II dose is docetaxel 70 mg/m2 and 17-AAG 500 mg/m2.

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Acknowledgments

We would like to thank Kin Tse for his assistance with data collection and analysis. National Cancer Institute grants P50-CA92629 and U01-CA69856 and the generous support of the Prostate Cancer Foundation.

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Correspondence to David B. Solit.

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Iyer, G., Morris, M.J., Rathkopf, D. et al. A phase I trial of docetaxel and pulse-dose 17-allylamino-17-demethoxygeldanamycin in adult patients with solid tumors. Cancer Chemother Pharmacol 69, 1089–1097 (2012). https://doi.org/10.1007/s00280-011-1789-3

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  • DOI: https://doi.org/10.1007/s00280-011-1789-3

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